Hepatitis C virus (HCV) is one of five viral agents known to cause viral hepatitis. HCV is a small RNA virus that resembles the flavi- or pestiviruses in its nucleotide sequence and genomic structure; Houghton et al., Hepatology, 14:381, 1991. Patients actively infected with HCV have HCV-RNA in blood which can be detected using sensitive assays employing reverse transcription followed by polymerase chain reaction amplification (RT-PCR); Weiner et al., Lancet, 335:1, 1990. HCV replicates largely, if not solely, in the liver and causes both acute and chronic hepatitis.
It is estimated by the Centers for Disease Control and Prevention that HCV is responsible for 160,000 new cases of acute hepatitis in the United States each year. While most patients are asymptomatic, approximately 25% of these patients may develop jaundice or other symptoms of hepatitis, and as many as 70% of these patients may progress to chronic liver disease as evidenced by persistent elevation of serum alanine aminotransferase (ALT) levels as well as continual presence of circulating HCV-RNA. In addition, progression of HCV infection to hepatocellular carcinoma has been well documented; Tong et al., WJM, 160.2:133-138, 1994. Epidemiology studies done by the Centers for Disease Control suggest that only 4% of HCV infections are transmitted by blood transfusions, 3% by hemodialysis, 10% by sexual transmission, 35% by intravenous drug use, and in 48% of cases, the mechanism of HCV transmission is unknown.
Interferons are a subclass of cytokines that exhibit both antiviral and antiproliferative activity. On the basis of biochemical and immunological properties, the naturally-occurring human interferons are grouped into three classes: interferon-alpha (leukocyte), interferon-beta (fibroblast) and interferon-gamma (immune). At least fourteen alpha interferons (grouped into subtypes A through H) having distinct amino acid sequences have been identified by isolating and sequencing DNA encoding these polypeptides. Alpha interferons have received considerable attention as potential therapeutic agents due to their antiviral and antitumor growth inhibition.
U.S. Pat. Nos. 4,695,623 and 4,897,471 disclose novel human interferon polypeptides having amino acid sequences which include common or predominant amino acids found at each position among naturally-occurring alpha interferon subtype polypeptides and are referred to as consensus interferons (IFN-con). The IFN-con amino acid sequences disclosed are designated IFN-con.sub.1, IFN-con.sub.2, and IFN-con.sub.3. The preparation of manufactured genes encoding IFN-con and the expression of said genes in E. coli are also disclosed. In vitro studies comparing the relative antiviral, antiproliferative, and natural killer cell activities of recombinant IFN-con with either leukocyte or other recombinant type-one interferons demonstrate that IFN-con displays significantly higher activity when compared on a mass basis; Ozes et al., J Interferon Research, 12:55-59, 1992.
U.S. Pat. No. 5,372,808 discloses methods of treatment of diseases using consensus interferon. It is shown that IFN-con, when used in the treatment of diseases susceptible to treatment by alpha interferons, does not cause the same degree of side effects in patients as do the alpha interferons. It was further shown that 3 to 5 times higher doses of IFN-con can be used, leading to enhanced therapeutic benefit, with substantially no corresponding increase in the frequency or severity of undesirable side effects.
HCV is one of several clinical indications for which interferons have been approved by the Food and Drug Administration, and IFN-.alpha. is currently licensed for use in chronic HCV; Hoofnagle et al., Interferon: Principles and Medical Applications, 1st Edition, Chap. 31, pgs 433-462, 1992. The types of responses that occur during IFN-.alpha. therapy can be characterized as: (1) a sustained complete response ("durable"), where patients serum ALT values begin to fall within the first months of treatment, are often normal by two to three months, and remain normal even after therapy is stopped. (these patients may also become negative for serum HCV RNA); (2) a transient complete response followed by relapse when therapy is stopped ("relapse"); (3) a partial or transient response, where patients serum ALT values decrease but do not become normal or become normal transiently and then rise despite continuation of interferon therapy ("partial response"); and (4) no response, where patients serum ALT activities remain elevated during interferon treatment ("non-response").
Use of IFN-.alpha. in sufficient dosage to yield clinical efficacy (i.e. at amounts of about 1.times.10.sup.6 units/treatment and above) is usually associated with a "flu-like" syndrome characterized by fever, headache, lethargy, arthalgias and myalgias; Tyring et al., Interferon: Principles and Medical Applications, 1st Edition, Section VIII., pgs 399-408, 1992. At higher doses, i.e. 5-10.times.10.sup.6 units/treatment and above, other toxicities become more frequent and may be dose-limiting. These effects include nausea, vomiting, diarrhea and anorexia; Id. at 403. Laboratory changes associated with high dose administration include relative leukopenia and thrombocytopenia and serum elevations in liver enzymes; Id.
The recommended IFN-.alpha. therapy for chronic HCV is 3-5 MU three times weekly either subcutaneously or intramuscularly for six to twelve months; see e.g., Davis et al., N Engl J Med., 321:1501-1506, 1989; Marcellin et al., Hepatology, 13:393-397, 1991; Causse et al., Gastroenterology, 101:497-502, 1991; Linsey et al., Hepatology, 18:106a, 1993. Generally, approximately fifty percent of IFN-.alpha. treated patients demonstrate normal serum ALT levels by the end of therapy. However, following cessation of IFN-.alpha. treatment, between 50-100% of the responding patients relapsed, resulting in a 0-25% "durable" ALT response rate, and a 0-25% "relapse" response rate. Unfortunately, there are no reliable means of predicting which patients are likely to respond to IFN-.alpha. and which of these will have a "durable" response.
In light of the shortcomings associated with IFN-.alpha. treatment of chronic HCV, investigators have set out to increase the response rate in chronic HCV, with several attempts focusing on the use of higher doses. Reports from these studies suggest that higher doses of IFN-.alpha., i.e., between 5 and 10 MU TIW to daily, may increase the long term ALT response rate; see e.g., Linsey et al., Hepatology, 18:106a, 1993; Hoofnagle et al., N Engl J Med., 315:1575-1578, 1989; Kakumu et al., Am J Gastroenterology, 85:655-659, 1990. However, because of the accompanying increase in toxicity, these higher doses are difficult to maintain and studies using doses up to 10 MU daily were only performed in patients who were hospitalized for this treatment; Iino et al., Dig Dis Sci., 38:612-618, 1993.
Other attempts have focused on IFN-.alpha. retreatment therapy. For example, Toyoda et al., Amer. Jour. of Gastroent., 89:9:1453-1457, 1994, analyzed the retreatment of chronic HCV with IFN-.alpha. to get the standpoint for the selection of patients to receive it. Toyoda et al. retreated 23 patients (15 relapses, 8 nonresponses) and reported that eight (34.8%) patients had normalized serum ALT values upon retreatment. All eight patients were patients from the "relapse" group who had had undetectable serum HCV-RNA at the end of their initial IFN-.alpha. treatment period. Based on their findings, Toyoda et al. concluded that selection of patients to receive retreatment requires careful consideration of genotype, HCV-RNA concentration, and the clinical response on initial treatment, and that interferon retreatment may be effective in "relapse" cases where the patient has undetectable serum HCV-RNA at the end of initial treatment.
Weiland et al., Scand J Infect Dis., 25:25-30, 1993, report the results of IFN-.alpha. retreatment of 10 "relapse" patients (all 10 patients had normalization of serum ALT levels during the nine month initial treatment). Weiland et al. concluded that a 6-month course of retreatment induced a normalization of serum ALT levels once again in most patients (6/10), and that HCV-RNA titers in serum fell to undetectable levels during retreatment, but that all patients relapsed again soon after treatment cessation, i.e., a second course of treatment fails to increase the number of patients with "durable" responses.
Marcellin et al., J. Infect Dis., 167:780, 1993, describe a study to assess the efficacy of retreatment with IFN-.alpha. in patients with chronic HCV who did not respond or who relapsed after an initial treatment. In the twelve patients retreated, retreatment with the same dose of the same interferon did not induce any "durable" responses. The overall rate of response to retreatment was not different from that observed with first treatment, i.e., relapsers responded but then relapsed again, and nonresponders to initial treatment were nonresponders to retreatment.
Marriott et al., J. Infect Dis., 166:1200-1201, 1992, evaluated the possible benefit of a second cycle of IFN administration in patients who were "relapse" or "non-response" patients to one cycle of IFN treatment. Of the retreated patients, 70% (14/20) had normalization of serum ALT values during retreatment, with 90% of the "relapse" patients having normalization of serum ALT values, and only 28% of "non-response" patients having normalization during retreatment. Of the 14 patients who normalized during retreatment, only 1 had a "durable" response. Marriott et al. conclude that a second cycle of therapy gave only a transitory benefit and was not useful in improving the rate of "durable" serum ALT normalization.
Schvarcz et al., Scand J Infect Dis., 23:413-420, 1991, report on the outcome of treatment with increased doses of interferon in "non-response" patients. The six "non-response" patients had been treated with 3 MU alpha-2b interferon thrice weekly (t.i.w.), and were retreated with 6 MU t.i.w. for at least 8 weeks. Schvarcz et al. report that none of the "non-response" patients normalized the serum ALT levels during the retreatment with the higher doses. Furthermore, with increased doses, side effects were much more pronounced.
Arase et al., J. of Gastroent., 29:299-304, 1994, studied the outcome of retreatment, using a human lymphoblastoid alpha interferon, of patients who failed to respond to initial interferon beta treatment. Specifically, Arase et al. studied the outcome of retreatment in relation to serum ALT levels after the initial treatment and concluded that high-dose (6 MU) and prolonged readministration of IFN-.alpha. may be a worthwhile strategy in patients with HCV subtype III or in those showing transient normalization of serum ALT levels and who are negative for serum HCV-RNA during or after their initial treatment. However, for those with HCV subtype II or persistently positive serum HCV-RNA and abnormal serum ALT levels during and after their initial treatment, retreatment with IFN-.alpha. is likely to fail.
Based on the teachings referenced above, it appears that retreatment with IFN-.alpha. has limited effectiveness in "relapse" patients, and little, if any, effectiveness in "non-response" patients. More importantly, retreatment fails to be useful in improving the rate of sustained serum ALT normalization, i.e. "durable" responses. It is clear then, that new approaches or modifications to IFN-.alpha. therapy of HCV are needed. Therefore, the object of this invention is a method for retreatment, using IFN-con, of patients suffering from HCV, whereby the rate of "durable" responses is increased.